Retinoblastoma Treatment (PDQ®)

Last Modified : 2019-12-03

General Information About Retinoblastoma

Retinoblastoma is a pediatric cancer that requires careful integration of multidisciplinary care. Treatment of retinoblastoma aims to save the patient's life and uses an individualized, risk-adapted approach to minimize systemic exposure to drugs, optimize ocular drug delivery, and preserve useful vision. For patients presenting with extraocular retinoblastoma, treatment with systemic chemotherapy and radiation therapy is likely to be curative. However, extraorbital disease requires intensive chemotherapy and may include consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue with or without radiation therapy. While a large proportion of patients with systemic extra–central nervous system (CNS) metastases can be cured, the prognosis for patients with intracranial disease is dismal.

Incidence

Retinoblastoma is a relatively uncommon tumor of childhood that arises in the
retina and accounts for about 3% of the cancers occurring in children younger
than 15 years.

Retinoblastoma is a cancer of the very young child; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years.
[1]
Thus, while the estimated annual incidence in the United States is approximately 4 cases per 1 million children younger than 15 years, the age-adjusted annual incidence in children aged 0 to 4 years is 10 to 14 cases per 1 million (approximately 1 in 14,000–18,000 live births).

Anatomy

Retinoblastoma arises from the retina, and it may grow under the retina and/or toward the vitreous cavity. Involvement of the ocular coats and optic nerve occurs as a sequence of events as the tumor progresses.

Focal invasion of the choroid is common, although the occurrence of massive invasion is usually limited to advanced disease. After invading the choroid, the tumor gains access to systemic circulation and creates the potential for metastases. Further progression through the ocular coats leads to invasion of the sclera and the orbit. Tumors that invade the anterior chamber may gain access to systemic circulation through the canal of Schlemm. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and CNS dissemination (refer to Figure 1).

Figure 1. Anatomy of the eye showing the sclera, ciliary body, canal of Schlemm, cornea, iris, lens, vitreous humor, retina, choroid, optic nerve, and lamina cribrosa. The vitreous humor is a gel that fills the center of the eye.

Screening

Recent consensus reports from the American Association of Ophthalmic Oncologists and Pathologists and the American Association for Cancer Research Childhood Cancer Predisposition Workshop describe surveillance guidelines for screening children at risk of developing retinoblastoma.
[2]
[3]

In children with a positive family history of retinoblastoma, early-in-life screening by fundus exam is performed under general anesthesia at regular intervals according to a schedule based on the absolute estimated risk, as determined by the identification of the RB1 mutation in the family and the presence of the RB1 mutation in the child.
[2]
[3]

Infants born to affected parents have a dilated eye examination under anesthesia as soon as possible in the first month of life, and a genetic evaluation is performed. Infants with a positive genetic test are examined under anesthesia on a monthly basis. In infants who do not develop disease, monthly exams continue throughout the first year; the frequency of those studies may be decreased progressively during the second and subsequent years. Screening exams can improve prognosis in terms of globe sparing and use of less intensive, ocular-salvage treatments in children with a positive family history of retinoblastoma (refer to Table 1 and Figure 2).
[2]
[3]

Table 1. Pretest Risk for Relatives to Carry the Mutant RB1 Allele of the Probanda,b

bPretest risk for RB1 mutation in family members of an affected child with retinoblastoma. Risk for RB1 mutant allele is shown as a percentage for unilateral and bilateral probands without family history of retinoblastoma.

cThird- and fourth-degree relatives of unilateral probands have calculated risks of 0.003% and 0.001%, respectively, which are less than the normal population risk of 0.007% (1 in 15,000 live births); therefore, the risk is stated at 0.007%.

Offspring (infant)

50

7.5

Parent

5

0.8

Sibling

2.5

0.4

Niece/nephew

1.3

0.2

Aunt/uncle

0.1

0.007c

First cousin

0.05

0.007c

General population

0.007

Figure 2. Management guidelines for childhood screening for retinoblastoma. The presented schedules are general guidelines and reflect a schedule for examinations in which no lesions of concern are noted. It may be appropriate to examine some children more frequently. Decisions regarding examination method, examination under anesthesia (EUA) versus nonsedated examination in the office, are complex and best decided by the clinician in discussion with the patient's family. The preference of the majority of the clinical centers involved in the creation of this consensus statement is reflected, but individual centers may make policy decisions based on available resources and expert clinician preference. Examination under anesthesia will be strongly considered for any child who is unable to participate in an office examination sufficiently to allow thorough examination of the retina. *A minority of clinical centers also prefer EUA for high- and intermediate-risk children (calculated risk >1%) from birth to 8 weeks of age. Reprinted from Ophthalmology, Volume 125, Issue 3, Alison H. Skalet, Dan S. Gombos, Brenda L. Gallie, Jonathan W. Kim, Carol L. Shields, Brian P. Marr, Sharon E. Plon, Patricia Chévez-Barrios, Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists, Pages 453–458, Copyright (2018), with permission from Elsevier.

It is common practice to use ophthalmic examinations to screen the parents and siblings of patients with retinoblastoma to exclude an unknown familial disease. Controversy exists regarding screening a child born to a parent who had unilateral retinoblastoma, but who has not had genetic testing.
[4]
This debate underscores the importance of genetic testing. In the future, if all patients with retinoblastoma undergo genetic testing, the assessment of risk to their offspring can be determined rather than estimated.

Clinical Presentation

Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life.

Most patients present with leukocoria, which is occasionally first noticed after a flash photograph is taken. Strabismus is the second most common presenting sign and usually correlates with macular involvement. Very advanced intraocular tumors present with pain, orbital cellulitis, glaucoma, or buphthalmos.

As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the preauricular and laterocervical lymph nodes, in the CNS, or systemically (commonly in the bones, bone marrow, and liver).

In the United States, children of Hispanic origin and children living in lower socioeconomic conditions have been noted to present with more advanced disease.
[5]

Diagnostic and Staging Evaluation

Diagnostic evaluation of retinoblastoma includes the following:

Eye examination. Intraocular retinoblastoma is usually diagnosed without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina. A very detailed documentation of the number, location, and size of tumors; the presence of retinal detachment and subretinal fluid; and the presence of subretinal and vitreous seeds must be performed.

Ocular ultrasound and magnetic resonance imaging (MRI). Bidimensional ocular ultrasound and MRI can be useful to differentiate retinoblastoma from other causes of leukocoria and in the evaluation of extrascleral and extraocular extension in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement; cautious interpretation of those findings is needed.
[6]

Reverse transcriptase–polymerase chain reaction (RT-PCR). The detection of the synthetase of ganglioside GD2 mRNA by RT-PCR in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease.
[7]

Evaluation for the presence of metastatic disease also needs to be considered in the subgroup of patients with suspected extraocular extension by imaging or high-risk pathology in the enucleated eye (i.e., massive choroidal invasion or involvement of the sclera or the optic nerve beyond the lamina cribrosa). Patients presenting with these pathological features in the enucleated eye are at high risk of developing metastases. In these cases, the following procedures may be performed:
[8]

Bone scintigraphy.

Bone marrow aspiration and biopsy.

Lumbar puncture.

Heritable and Nonheritable Forms of Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

Heritable retinoblastoma may manifest as unilateral or bilateral
disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.
[9]
[10]
All children with bilateral disease
and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.

Children with heritable retinoblastoma tend to be diagnosed at a younger age than are children with the nonheritable form of the disease.
It was thought that unilateral retinoblastoma in children younger than 1 year raises concern for the presence of heritable disease,
whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.
[11]
However, in a retrospective single-institution report of 182 patients with unilateral retinoblastoma, patients with a positive genetic result (n = 32) were diagnosed at a mean age of 26 months, and patients without genetic results were diagnosed at a mean age of 22 months (P = .31).
[12]

The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.
[13]
[14]
A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods.
[15]

Other recurring genomic changes that occur in a small minority of tumors include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification.
[13]
[14]
[15]
A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MYCN amplification.
[14]
The functional status of the retinoblastoma protein (pRb) is inferred to be inactive in retinoblastoma with MYCN amplification. This suggests that inactivation of RB1 by mutation or inactive pRb is a requirement for the development of retinoblastoma, independent of MYCN amplification.
[16]

Genetic Testing

Blood and tumor samples can be tested to determine whether a patient with retinoblastoma has a germline or somatic mutation in the RB1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation with targeted sequencing.

A multistep assay that includes the following may be performed for a complete genetic evaluation of the RB1 gene:
[17]

Methylation analysis of the RB1 promoter region on DNA isolated from the tumor.

In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected; more exhaustive techniques such as karyotyping, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed. Deep (2500x) sequencing of an RB1 genomic amplicon from lymphocyte DNA can reveal low-level mosaicism.
[18]
Because mosaicism is caused by a postzygotic mutation, such a finding obviates the need for serial examination of siblings under anesthesia. Current technologies will not discover some mosaic mutations at very low levels of amplification, mutations outside of the RB1 coding exons or the flanking intronic regions, mutations not found in lymphocytes but in other tissues (mosaic), or mosaic large rearrangements of RB1.
[18]
Combining the above techniques, a germline mutation may be detected in more than 90% of patients with heritable retinoblastoma.
[19]
[20]
[21]

The absence of detectable somatic RB1 mutations in approximately 3% of unilateral, nonheritable retinoblastoma cases suggests that alternative genetic mechanisms may underlie the development of retinoblastoma.
[22]
In one-half of these cases, high levels of MYCN amplification have been reported; these patients had distinct, aggressive histologic features and a median age at diagnosis of 4 months.
[14]
However, MYCN amplification has also been reported to coexist with RB1 mutations.
[16]
In another small subset of tumors without detectable somatic RB1 mutations, chromothripsis is responsible for inactivating the RB1 gene.
[15]

Genetic Counseling

Genetic counseling is an integral part of the management of patients with retinoblastoma and their families, regardless of clinical presentation. Counseling includes a discussion of the main forms of retinoblastoma, which assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members.
[19]
Counseling also includes guidance towards appropriate screening for both patients and their families, especially if the risk of developing a second primary malignancy is increased.

Genetic counseling, however, is not always straightforward. Approximately 10% of children with retinoblastoma have somatic genetic mosaicism, which contributes to the difficulty of genetic counseling.
[23]
In addition, for one specific mutation, the risk of retinoblastoma in a sibling may depend partly on whether the mutation is inherited from the mother or father.
[24]
(Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Postdiagnosis Surveillance

Children with a germline RB1 mutation may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently. It is common practice for examinations to occur every 2 to 4 months for at least 28 months.
[25]
The interval between exams is based on the stability of the disease and age of the child (i.e., less frequent visits as the child ages).

A proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye. Periodic examinations of the unaffected eye are performed until the germline status of the RB1 gene is determined.

Because of the poor prognosis for patients with trilateral retinoblastoma, screening with neuroimaging until age 5 years is a common practice in the monitoring of children with the heritable form of the disease. (Refer to the Trilateral retinoblastoma section in the Causes of Retinoblastoma-Related Mortality section of this summary for more information.)

Causes of Retinoblastoma-Related Mortality

While retinoblastoma is a highly curable disease, the challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness, and other serious effects of treatment that reduce the patient's life span or quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality in the first and subsequent decades of life.

In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral disease and the implementation of neuroimaging screening, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.
[26]
Second neoplasms are the most common cause of death and contribute to about 50% of deaths in patients with bilateral disease and genetically defined heritable retinoblastoma.
[27]
[28]
[29]

Trilateral retinoblastoma

Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable retinoblastoma. It is defined by the development of an intracranial
midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months.
[30]

Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life.
[31]
Because of the poor prognosis for patients with trilateral retinoblastoma and the apparent improved survival with early detection and aggressive treatment, screening with routine neuroimaging could potentially detect most cases within 2 years of first diagnosis.
[30]
Routine baseline brain MRI is recommended at diagnosis because it may detect trilateral retinoblastoma at a subclinical stage. In a small series, the 5-year overall survival rate was 67% for patients with tumors that were detected at baseline, compared with 11% for the group with a delayed diagnosis.
[32]

Although it is not clear whether early diagnosis can impact survival, screening with MRI has been recommended as often as every 6 months for 5 years for patients suspected of having heritable disease or those with unilateral disease and a positive family history.
[33]
Computed tomography scans are generally avoided for routine screening in these children because of the risk related to ionizing radiation exposure.

A cystic pineal gland, which is commonly detected by surveillance MRI, needs to be distinguished from a cystic variant of pineoblastoma. In children without retinoblastoma, the incidence of pineal cysts has been reported to be 55.8%.
[34]
In a case-control study that included 77 children with retinoblastoma and 77 controls, the incidence of pineal cysts was similar (61% and 69%, respectively), and the size and volume of the pineal gland was not significantly different between the groups.
[35]
However, a cystic component has been described in up to 57% of patients with histologically confirmed trilateral retinoblastoma.
[32]
An excessive increase in the size of the pineal gland seems to be the strongest parameter indicating a malignant process.
[35]

Subsequent neoplasms (SNs)

Survivors of retinoblastoma have a high risk of developing SNs.

Factors that influence the risk of SNs include the following:

Heritable retinoblastoma.

Patients with heritable retinoblastoma have a markedly increased
incidence of SNs, independent of treatment with radiation therapy.
[27]
[28]
[36]
In a German series of 643 patients with heritable retinoblastoma, chemotherapy with or without radiation therapy was the only significant risk factor for the onset of second cancers outside the periorbital region.
[28]
A possible association between the type of RB1 mutation and incidence of SNs may exist, with complete loss of RB1 activity associated with a higher incidence of SNs.
[37]
With the increase in survival of patients with heritable retinoblastoma, it has become apparent that they are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described.
[38]
[39]

In a large series from two institutions, 2,053 patients with retinoblastoma (diagnosed between 1914–2016) were identified, with a maximum of 70 years of follow-up. Most deaths occurred in patients with hereditary retinoblastoma (518 of 1,129), and 267 of these deaths were caused by SNs. Increased risk of death resulting from cancers of the pancreas, large intestines, and kidney were reported. Overall risk of SNs was greater for patients who were treated with radiation therapy and chemotherapy compared with patients who were treated with radiation therapy alone, although patterns varied by organ site. In a new cohort of 143 retinoblastoma survivors diagnosed between 1997 and 2006, continued improvements in mortality were seen.
[29]
[Level of evidence: 3iiB] For patients with nonhereditary retinoblastoma, only 27 deaths in 924 patients were attributed to SNs.

Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline mutation are at a slightly higher risk of developing an SN than are those with a de novo mutation; this increase appears to be most significant for melanoma.
[40]

Past treatment for retinoblastoma with radiation therapy.

The cumulative incidence of SNs was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50
years after diagnosis of retinoblastoma—a rate of about 1% per year.
[41]

A German series of 633 patients with heritable retinoblastoma demonstrated a 5-year survival of 93%; however, 40 years later, only 80% of patients survived, with most succumbing to radiation-induced SNs (hazard ratio, approximately 3).
[42]
Other studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the SN rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients.
[43]

In a nonrandomized study that compared two contemporary cohorts of patients with hereditary retinoblastoma who were treated with either photon (n = 31) or proton (n = 55) therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation; P = .015).
[44]
A longer follow-up will be required to further define the risk of SNs associated with proton radiation.

The most common SN is sarcoma, specifically osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although most are radiation induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas; a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third of SNs occur outside the radiation field.
[36]
[41]
[43]
[45]

Age at time of radiation therapy.

The risk of SNs also appears to depend on the patient's age at the time that external-beam radiation therapy (EBRT) is administered, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.
[43]
[46]
[47]

Previous SN.

Patients who survive SNs are at a sevenfold increased risk of developing another SN.
[48]
The risk increases an additional threefold for patients treated with radiation therapy.
[49]

The issue of balancing long-term tumor control with the consequences of chemotherapy is unresolved. Most patients who receive chemotherapy are exposed to etoposide, which has been associated with secondary leukemia in patients without a predisposition to cancer, but at modest rates when compared with the risks associated with EBRT in heritable retinoblastoma.

Despite the known increased risk of acute myeloid leukemia (AML) associated with the use of etoposide, patients with heritable retinoblastoma are not at an increased risk of developing this SN.
[50]
[51]
[52]
An initial report conducted by informal survey methods described 15 patients who developed AML after chemotherapy. One-half of the patients also received radiation therapy.
[51]
This finding has not been substantiated by formal studies. In a single-institution study of 245 patients who received etoposide, only 1 patient had acute promyelocytic leukemia after 79 months.
[50]
Additionally, the Surveillance, Epidemiology, and End Results (SEER) program calculated standardized incidence rates for secondary hematopoietic malignancies in 34,867 survivors of childhood cancer. The observed-to-expected ratio of secondary AML in patients treated for retinoblastoma was zero.
[53]

Survival from SNs is certainly suboptimal and varies widely across studies.
[38]
[54]
[55]
[56]
[57]
[58]
However, with advances in therapy, it is essential that all SNs in survivors of retinoblastoma be treated with curative intent.
[59]

Late Effects From Retinoblastoma Therapy

In a report from the Retinoblastoma Survivor Study (N = 470), 87% of survivors of retinoblastoma (mean age, 43 years; median follow-up, 42 years) had at least one medical condition and 71% had a severe or life-threatening condition. The adjusted relative risk of a chronic condition in survivors, compared with nonretinoblastoma controls, was 1.4 (P < .01); the relative risk of a grade 3 or 4 condition was 7.6 (P < .01). After excluding ocular conditions and SNs, this excess risk was found to persist only for patients with bilateral disease.
[60]

As previously discussed, patients with heritable retinoblastoma have an increased incidence of SNs. (Refer to the Subsequent neoplasms [SNs] section of this summary for more information.) Other late effects that may occur after treatment for retinoblastoma include the following:

Diminished orbital growth.

Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.
[61]
Asymmetry of orbital size that develops after enucleation is greater in younger children and infants, but enucleation after age 3 years does not result in orbital asymmetry.
[62]

Visual-field deficits.

Patients with retinoblastoma demonstrate a variety of long-term visual-field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method.
[63]

One study of visual acuity after treatment with systemic chemotherapy and local ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had a final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin of at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.
[64]

While two large studies that included children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed an incidence of treatment-related hearing loss of lower than 1%,
[65]
[66]
a separate series documented some degree of hearing loss in 17% of patients.
[67]
In the latter study, age younger than 6 months at the time of treatment and higher carboplatin systemic exposures correlated with an increased risk of ototoxicity.
[67]
[68]

Sirin S, de Jong MC, Galluzzi P, et al.: MRI-based assessment of the pineal gland in a large population of children aged 0-5 years and comparison with pineoblastoma: part II, the cystic gland. Neuroradiology 58 (7): 713-21, 2016.[PUBMED Abstract]

Tumor Pathology of Retinoblastoma

Maturing cone precursor cells appear to be the cell of origin in human retinoblastoma.
[1]
[2]
Microscopically, the appearance of retinoblastoma depends on the degree of differentiation. Undifferentiated retinoblastoma is composed of small, round, densely packed cells with hypochromatic nuclei and scant cytoplasm. Several degrees of photoreceptor differentiation have been described and are characterized by distinctive arrangements of tumor cells, as follows:

Flexner-Wintersteiner rosettes

are specific to retinoblastoma; these structures consist of a cluster of low columnar cells arranged around a central lumen that is bounded by an eosinophilic membrane analogous to the external membrane of the normal retina. The lumen contains rosettes that are seen in 70% of tumors.

Homer Wright rosettes

are composed of irregular circlets of tumor cells arranged around a tangle of fibrils with no lumen or internal-limiting membrane. Homer Wright rosettes are infrequently seen in retinoblastoma and are most often seen in other neuroblastic tumors, such as neuroblastoma and medulloblastoma.

Retinoblastomas
are characterized by marked cell proliferation, as evidenced by high mitosis
counts, extremely high MIB-1 labeling indices, and strong diffuse nuclear immunoreactivity for CRX, a useful marker to discriminate retinoblastoma from other malignant, small, round cell tumors.
[3]
[4]

Cavitary retinoblastoma, a rare variant of retinoblastoma, has ophthalmoscopically visible lucent cavities within the tumor. The cavitary spaces appear hollow on ultrasonography and hypofluorescent on angiography. Histopathologically, the cavitary spaces have been shown to represent areas of photoreceptor differentiation.
[5]
These tumors have been associated with minimal visible tumor response to chemotherapy, which is thought to be a sign of tumor differentiation.
[6]

A pathologist experienced in ocular pathology and retinoblastoma should examine the enucleated specimen, particularly to determine risk features of extraocular dissemination (refer to the Treatment of Intraocular Retinoblastoma section of this summary for more information).

Staging and Grouping Systems for Retinoblastoma

The staging of patients with retinoblastoma requires close coordination of radiologists, pediatric oncologists, and ophthalmologists. Several staging and grouping systems have been proposed for retinoblastoma.
[1]
Overall assessment of retinoblastoma extension is documented by staging systems; the extent of intraocular disease, which is relevant for ocular salvage, is documented by grouping systems. For treatment purposes, retinoblastoma is categorized
into intraocular and extraocular disease.

Intraocular Retinoblastoma

Intraocular retinoblastoma is localized to the eye; it may be confined to the
retina or may extend to involve other structures such as the choroid, ciliary body, anterior chamber, and optic nerve head. Intraocular retinoblastoma, however, does not extend beyond
the eye into the tissues around the eye or to other parts of the body.

Extraocular Retinoblastoma

Extraocular retinoblastoma extends beyond the eye. It may be confined to
the tissues around the eye (orbital retinoblastoma), it may have spread to the central
nervous system, or it may have spread systemically to the bone marrow or lymph nodes (metastatic retinoblastoma).

Staging Systems

American Joint Committee on Cancer (AJCC) staging system

Several staging systems have been proposed over the years. The newest standard for state-mandated cancer reporting to the North American Association of Cancer Registries requires AJCC staging, according to the 8th edition of the staging manual. This affects cases diagnosed in 2018 and thereafter. Retinoblastoma staging is the first to acknowledge the role of genetic predisposition by incorporating an H category. H1 refers to patients with bilateral or trilateral retinoblastoma, a family history of retinoblastoma, or the presence of an RB1 mutation.
[2]

International Retinoblastoma Staging System (IRSS)

The more simplified IRSS has been proposed by an international consortium of ophthalmologists and pediatric oncologists;
[3]
it is more widely used in the clinical setting than the AJCC staging system (refer to Table 2). A retrospective German study found that the IRSS predicted survival in 633 children with heritable retinoblastoma, 582 of whom presented with IRSS stage 0 or I disease.
[4]

International Classification of Retinoblastoma

The International Classification of Retinoblastoma grouping system was developed with the goal of providing a simpler, more user-friendly classification that is more applicable to current therapies. This newer system is based on the extent of tumor seeding within the vitreous cavity and subretinal space, rather than on tumor size and location (refer to Table 3). This system seems to be a better predictor of treatment success.
[5]
[6]
[7]
[8]
The International Classification of Retinoblastoma system may also help predict high-risk histopathology. In a study of more than 500 patients with retinoblastoma, histopathologic evidence of high-risk disease was noted in 17% of Group D eyes and 24% of Group E eyes. This can be helpful in counseling parents regarding the potential need for postoperative systemic therapy.
[9]

Table 3. The International Classification of Retinoblastoma Grouping System

Group

Definition

Group A

Small intraretinal tumors away from the foveola and disc.

All tumors are 3 mm or smaller in greatest dimension, confined to the retina and

All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc.

Group B

All remaining discrete tumors confined to the retina.

All other tumors confined to the retina not in Group A.

Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding.

Tumor located closer than 3 mm to the optic nerve or fovea.

Group C

Discrete local disease with minimal subretinal or vitreous seeding.

Tumor(s) are discrete.

Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina.

Local fine vitreous seeding may be present close to the discrete tumor.

Local subretinal seeding less than 3 mm (2 DD) from the tumor.

Group D

Diffuse disease with significant vitreous or subretinal seeding.

Tumor(s) may be massive or diffuse.

Subretinal fluid present or past without seeding, involving up to total retinal detachment.

Diffuse or massive vitreous disease may include greasy seeds or avascular tumor masses.

Diffuse subretinal seeding may include subretinal plaques or tumor nodules.

Reese-Ellsworth Classification for Intraocular Tumors

Reese and Ellsworth developed a classification system for
intraocular retinoblastoma that has been shown to have prognostic significance
for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy were the primary treatment options. However, developments in the conservative management of intraocular retinoblastoma have made the Reese-Ellsworth grouping system less predictive for eye salvage and less helpful in guiding treatment.
[7]
This grouping system is seldom used and serves largely as a historical reference.

Treatment Option Overview for Retinoblastoma

Treatment planning by a multidisciplinary team of cancer specialists—including a pediatric oncologist, ophthalmologist, and radiation oncologist—with
experience treating ocular tumors of childhood is required to optimize treatment outcomes.
[1]
Evaluation at specialized centers is highly recommended before the initiation of treatment to improve the likelihood of ocular salvage and vision preservation.

Many treatments considered to be standard of care have not been studied in a randomized fashion.

Treatment of retinoblastoma depends on the intraocular and extraocular disease burden, disease laterality, germline RB1 gene status, and the potential for preserving vision. For patients presenting with intraocular disease, particularly those with bilateral eye involvement, a conservative approach consisting of tumor reduction with intravenous or ophthalmic artery chemotherapy, coupled with aggressive local therapy, may result in high ocular salvage rates.
[2]
Radiation therapy, one of the most effective treatments in retinoblastoma, is usually reserved for cases of intraocular or extraocular disease progression.

A risk-adapted, judicious combination of the following therapeutic options should be considered:

Enucleation

Upfront removal of the eye is indicated for large tumors filling the vitreous for which there is little or no likelihood of restoring vision, in cases of extension to the anterior chamber, or in the presence of neovascular glaucoma. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation.
[3]
[Level of evidence: 3iiA] Enucleation is also used as a salvage treatment in cases of disease progression or recurrence in patients receiving eye-salvage management. The pathology specimen must be carefully examined to identify patients who are at high risk of extraocular dissemination and who may require adjuvant chemotherapy.

Enucleation in patients younger than 3 years does not allow for the proper enlargement of the orbit during subsequent development, causing asymmetry of the final orbital size.
[4]

Local Treatment (Cryotherapy, Laser Therapy, and Brachytherapy)

For patients undergoing eye-salvage treatment, aggressive local therapy is always required. Local treatment is administered by the ophthalmologist directly to the tumor.

Cryotherapy:

Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. Cryotherapy is used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the
anterior portion of the retina.

Laser therapy:

Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation (argon laser), in which the laser was applied around the tumor to target the tumor vasculature, has given way to thermotherapy (diode laser). Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.
[5]
[6]

Brachytherapy (plaque radiation therapy):

For larger tumors that are not amenable to cryotherapy or laser therapy, brachytherapy can provide an effective means for local control (refer to the Radiation Therapy section of this summary for more information).

Systemic Chemotherapy

Systemic chemotherapy plays a role in the following:

Adjuvant setting for patients with high-risk pathology.

Different regimens have been used in the management of patients with high-risk pathology in the enucleated specimen. Most regimens include a three-drug combination of vincristine, etoposide, and carboplatin, either alone or alternating with cyclophosphamide and an anthracycline.
[7]
[8]
[9]
[10]

Treatment of patients with extraocular and metastatic disease.

Patients with extraocular disease benefit from more intensive therapy. While a standard treatment has not been determined, responses to cisplatin-based regimens, with consolidation using high-dose chemotherapy and autologous hematopoietic stem cell rescue for patients with extraorbital disease, have been reported.
[11]
[12]
[13]
[14]

During the past two decades, the standard of care has been systemic chemotherapy to reduce tumor
volume (chemoreduction) to facilitate the use of local treatments and to avoid the long-term effects of radiation
therapy.
[15]
The success rate for eye salvage varies from center to center, but overall good ocular outcomes are consistently obtained for discrete tumors without vitreous seeding.

Chemotherapy may also be continued or initiated with concurrent local control. Eye grouping, as defined by the International Classification of Retinoblastoma, is the best predictor of ocular salvage using this approach, with salvage rates ranging from 60% to 100%.
[16]

Prolonged chemotherapy instead of enucleation, in the context of persistent disease activity, should be used cautiously because this approach has been associated with an increased risk of metastatic disease.
[16]
;
[17]
[Level of evidence: 3iiDii]

Treatment of patients with hereditary retinoblastoma.

In patients with hereditary retinoblastoma, younger patients and those with a positive family history are more likely to develop new tumors. Chemotherapy may treat small, previously undetected lesions by slowing their growth, and this may improve overall salvage with local therapy.
[18]

Direct delivery of chemotherapy into the eye via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage.

Melphalan is the most common and most effective agent used for intra-arterial chemotherapy. It is often combined with topotecan or carboplatin when responses are suboptimal or there is very advanced intraocular disease.
[19]
[20]

For patients with treatment-naive eyes, the 2-year radiation-free ocular survival rate is 86% to 90%.
[19]
[20]
Outcome after intra-arterial chemotherapy correlates with the extent of intraocular burden, as follows:

Patients with early intraocular disease (Group B and C eyes) have an excellent outcome, with ocular salvage rates exceeding 85%, and may be treated with single-agent therapy.
[20]

Patients with Group D eyes have a worse outcome;
[20]
however, ocular salvage rates greater than 80% have been reported in specialized centers.
[19]
[21]
For patients with very advanced intraocular disease, an alternative treatment is the use of systemic chemotherapy followed by consolidation with intra-arterial melphalan.
[22]

Ocular salvage rates when intra-arterial chemotherapy administration is used as salvage treatment for patients with recurrent or progressive disease are consistently lower, with globe survival rates of 50% to 75%.
[19]
[20]
[21]
Best results are reported using a more intensive three-drug regimen with melphalan, topotecan, and carboplatin.
[23]

Patients with bilateral disease can undergo tandem intra-arterial chemotherapy administration.
[24]
In those circumstances, patients are at higher risk of systemic toxicity caused by melphalan exposure,
[25]
and single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure.
[26]
For neonates and very young infants in whom the cannulization of the ophthalmic artery is not feasible, bridge treatment with single-agent systemic carboplatin until the infant is aged 3 months or weighs 6 kg, followed by consolidation with intra-arterial chemotherapy, has been shown to be very effective, with a 1-year radiation-free ocular survival rate of 95%.
[27]

The addition of intravitreal chemotherapy to intra-arterial chemotherapy appears to markedly improve the overall effectiveness in eyes with vitreous seeds, especially those with vitreous seed clouds (refer to the Intravitreal Chemotherapy section of this summary for more information).
[19]
[28]
[29]
In patients presenting with total retinal detachment, ophthalmic artery chemosurgery has been shown to promote retinal reattachment.
[30]

Complications related to intra-arterial chemotherapy include the following:
[20]

Major vascular complications related to the procedure are very rare; no strokes or significant acute neurological events have been reported by the most experienced groups.
[19]
[20]
[32]
However, stenosis of the ophthalmic artery and occlusion of the retinal artery have been documented;
[32]
the risk of thrombosis is significantly increased in children with thrombophilia.
[33]

The impact of the intraocular vascular changes on vision has not been fully assessed because of the young age of the first cohorts of patients treated. Most patients do not have substantial electroretinographic changes,
[34]
and preservation of central vision has been reported.
[35]
A proportion of patients with abnormal electroretinograms (ERGs) with or without retinal detachment may have improved ERGs in the years after intra-arterial chemotherapy.
[36]
However, in patients with heavily pretreated eyes, intensive intra-arterial chemotherapy may result in worsening of retinal function.
[23]

Another risk associated with intra-arterial chemotherapy is the exposure to ionizing radiation during fluoroscopy. Mean total radiation doses of 42.3 mGy have been reported in very experienced centers.
[37]
After multiple procedures, cumulative doses can reach 0.1 to 0.2 Gy, which can be cataractogenic and potentially carcinogenic in this susceptible population.
[38]
There is no increase in the incidence of second malignancies;
[39]
[40]
however, longer follow-up will be required to fully ascertain the risks associated with the procedure.

The risk of metastatic progression with direct ocular delivery of chemotherapy appears to be very low;
[2]
however, up to 20 cases of patients treated with intra-arterial chemotherapy who subsequently developed metastases have been reported.
[20]

Intravitreal Chemotherapy

Studies suggest that direct intravitreal injection of melphalan or topotecan may be effective in controlling active vitreous seeds.
[41]
[42]
;
[43]
[Level of evidence: 3iiDi];
[44]
[Level of evidence: 3iiiDiii] A retrospective study of 264 eyes (250 children) treated with intravitreal melphalan for vitreous seeds over a two-decade period reported a 68% complete remission rate. There was a low incidence of extraocular spread as a result of the injection that occurred in children with high-risk features.
[45]
[Level of evidence: 3iiD]

Because of initial concerns about the potential for tumor dissemination, the use of intravitreal chemotherapy was limited. However, additional reports have estimated that the proportion of patients with extraocular tumor spread, as the result of intravitreal injection, is negligible.
[46]
[47]
While this procedure is safe and well tolerated, recent studies have shown a direct correlation between the number of injections and a decrease in retinal function, as measured by ERG.
[47]
;
[48]
[Level of evidence: 3iiiDiv]

Preliminary data seem to support that intra-arterial chemotherapy plus intravitreal chemotherapy (as needed for vitreous seeding) may improve globe salvage in eyes with advanced retinoblastoma when compared with children who were treated in earlier years with intra-arterial chemotherapy alone.
[47]
;
[28]
[Level of evidence: 3iiDii] Compared with the children treated in the earlier era, children treated in the later era received a combination of intra-arterial and intra-vitreal chemotherapy, which demonstrated shorter time to regression, fewer recurrences, fewer enucleations, and no increased toxicity, including no difference in loss of retinal function as measured by ERG.
[29]
[Level of evidence: 3iiDiv]

As experience with the use of intra-vitreal chemotherapy expands, studies have demonstrated its efficacy in controlling subretinal seeds and recurrent retinal tumors, suggesting a potential role beyond the control of vitreous seeds as an adjunctive therapy in the globe-sparing treatment of retinoblastoma.
[49]

Subtenon Chemotherapy (Subconjunctival Chemotherapy)

Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this treatment is often used in ocular salvage approaches, particularly when there is a high vitreal tumor burden. Carboplatin is administered by the treating ophthalmologist into the subtenon space, and it is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for patients with vitreous disease.
[50]
Responses have also been noted with subtenon topotecan.
[29]
[51]

With the development of new treatments for retinoblastoma, such as intra-arterial and intravitreal delivery of chemotherapy, subtenon chemotherapy is being used less often in the clinical setting.

Radiation Therapy

EBRT:

Retinoblastoma is a very radiosensitive malignancy. EBRT doses ranging from 35 Gy to 46 Gy usually result in long-term remissions.
Because of the need to sedate young children and the intricacies of field
planning, special expertise in pediatric radiation therapy is important.
Radiation therapy is used in cases of progression after conservative approaches, in patients with extraocular extension, and as part of the management of patients with metastatic disease.

Newer methods of delivering EBRT are being applied in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy and proton-beam radiation therapy (charged-particle radiation therapy).
[52]
[53]
[54]
[55]
Preliminary data suggest that proton radiation therapy is associated with a lower risk of radiation-induced malignancy in survivors of heritable retinoblastoma. In a nonrandomized study that compared two contemporary cohorts of patients with heritable retinoblastoma who were treated with either photon or proton radiation therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, P = .015).
[56]

EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. EBRT also increases the risk of SNs in children with heritable retinoblastoma.

Brachytherapy (plaque radiation therapy):

Indications for plaque radiation therapy include solitary tumors with a diameter ranging between 6 mm and 15 mm, tumor thickness of 10 mm or less, and tumor location of more than 3 mm from the optic disc or fovea. The most commonly used radioisotope is iodine I 125, although others such as iridium Ir 192 and ruthenium Ru 106 are also effective. In combination with the appropriate use of chemotherapy and other forms of focal consolidation, brachytherapy can be very effective in the treatment of localized retinal tumors that are not amenable to other means of local therapy.
[57]
[58]
[59]

Special Considerations for the Treatment of Children with Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.
[60]
Children and adolescents with
cancer should be referred to medical centers that have a multidisciplinary team
of cancer specialists with experience treating the cancers that occur during
childhood and adolescence. This multidisciplinary team approach is particularly important in the management of retinoblastoma; this approach incorporates the skills
of the following health care professionals and others to ensure that children
receive treatment, supportive care, and rehabilitation that will provide
optimal survival and quality of life:

An ophthalmologist with extensive experience in the treatment of children with retinoblastoma.

Primary care physicians.

Pediatric surgical subspecialists.

Radiation oncologists.

Pediatric medical oncologists/hematologists.

Rehabilitation specialists.

Pediatric nurse specialists.

Social workers.

Guidelines for pediatric cancer centers
and their role in the treatment of pediatric patients with cancer have been
outlined by the American Academy of Pediatrics.
[61]
At these pediatric cancer
centers, clinical trials are available for most types of cancer
that occur in children and adolescents, and the opportunity to participate in
these trials is offered to most patients and their families. Clinical trials for
children and adolescents with cancer are generally designed to compare
potentially better therapy with therapy that is currently accepted as standard.
Most of the progress made in identifying curative therapies for
childhood cancers has been achieved through clinical trials. Information about
ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.
[60]
[62]
[63]
Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.
[60]
[62]
[63]
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Chemoreduction with either systemic or ophthalmic artery infusion chemotherapy with or without intravitreal chemotherapy.

Local treatments, including cryotherapy, thermotherapy, and plaque radiation therapy.

Enucleation with or without adjuvant chemotherapy

Because unilateral disease is usually massive and often there is no
expectation that useful vision can be preserved, up-front surgery (enucleation) is
commonly performed. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These

high-risk features

Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology.
[6]

High-risk pathology has been associated with the presence of minimal dissemination in bone marrow and cerebrospinal fluid using quantitative polymerase chain reaction for detection of CRX or GD2 synthase. In a group of 96 children with nonmetastatic retinoblastoma and high-risk pathology, the 3-year disease-free survival was 78% for patients with detectable minimal dissemination, compared with 98% for those without detectable disease (P = .004).
[7]

Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used to prevent the development of metastatic disease in patients with certain high-risk features assessed by pathologic review after enucleation.
[3]
[8]
[9]
;
[10]
[Level of evidence: 2A]

Conservative ocular salvage approaches

Conservative ocular salvage approaches, such as systemic chemotherapy and local-control treatments, may be offered in an attempt to save the eye and preserve vision.
[11]
Ocular salvage rates correlate with intraocular grouping. While the possibility of saving the eye without the use of external-beam radiation therapy (EBRT) exceeds 80% for children with early intraocular disease, the ocular outcomes for children with advanced intraocular disease are poor, with less than 40% ocular salvage rates, even after the use of EBRT.
[12]

Thus, caution must be exerted with extended systemic chemotherapy administration and delayed enucleation when tumor control does not appear to be possible, particularly for Group E eyes. Pre-enucleation chemotherapy for eyes with advanced intraocular disease may result in downstaging and underestimate the pathological evidence of extraretinal and extraocular disease, thus increasing the risk of dissemination.
[13]

The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than does systemic chemotherapy for chemoreduction, particularly for Group D eyes.
[14]
[15]
;
[16]
[Level of evidence: 3iiDiv] In the setting of a multidisciplinary state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates of approximately 80% to 90% for patients with advanced intraocular unilateral retinoblastoma.
[15]
[16]
[17]
[18]
(Refer to the Ophthalmic Artery Infusion of Chemotherapy [Intra-arterial Chemotherapy] section of this summary for more information.)

Because a proportion of children who present with unilateral retinoblastoma
will eventually develop disease in the opposite eye, these children undergo genetic counseling and testing and periodic examinations
of the unaffected eye, regardless of the treatment they receive. Asynchronous bilateral disease occurs most
frequently in patients with affected parents and in children diagnosed during the first months of life.

Treatment of Bilateral Intraocular Retinoblastoma

The goal of therapy for bilateral retinoblastoma is ocular and vision preservation and the delay or avoidance of EBRT and enucleation.

Treatment options for bilateral intraocular retinoblastoma include the following:

Enucleation for large intraocular tumors, followed by pathology-based, risk-adapted chemotherapy when the eye and vision cannot be saved.

Conservative ocular salvage approaches when the eye and vision can be saved.

Chemoreduction with either systemic or ophthalmic artery infusion chemotherapy with or without intravitreal chemotherapy.

Local treatments, including cryotherapy, thermotherapy, and plaque radiation therapy.

EBRT.

Intraocular tumor burden is usually asymmetric, and treatment is dictated by the most advanced eye.
Systemic therapy is generally selected on the basis of the eye with more extensive disease. Treatment options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close monitoring for response and aggressive local treatment is usually the treatment of choice.
EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic or intra-arterial chemotherapy and local consolidation.
[19]

A number of large centers have published trial results that used systemic chemotherapy in conjunction with aggressive local consolidation for patients with bilateral disease.
[20]
The backbone of chemoreduction has generally been carboplatin, etoposide, and vincristine. While the less toxic combination of vincristine and carboplatin can provide disease control for a significant proportion of patients, ocular salvage appears to be superior when etoposide is included in the regimen.
[21]
[Level of evidence: 1iiDiii] Similar results were achieved in one single-institution study when topotecan was substituted for etoposide in a combination regimen.
[22]
[Level of evidence: 3iiA] Using this approach, the International Classification of Retinoblastoma grouping system has been proven to predict ocular survival, with globe salvage rates usually exceeding 80% for Groups A and B, and 40% to 80% for Groups C and D, although EBRT may be required in more advanced intraocular cases.
[23]
;
[20]
[22]
[Level of evidence: 3iiA]

For patients with large intraocular tumor burdens with subretinal or vitreous seeds (Group D eyes), the administration of higher doses of carboplatin coupled with subtenon carboplatin, and the addition of lower doses of EBRT (36 Gy) for patients with persistent disease has been explored. Using this intensive approach, eye survival may approach a rate of 70% at 60 months.
[24]
[Level of evidence: 2Div]

The use of prolonged systemic chemotherapy for Group E eyes to avoid or delay enucleation has been associated with lower disease-specific survival.
[13]
[Level of evidence: 3iiiB]

Delivery of chemotherapy via ophthalmic artery cannulation with the addition of intra-vitreal chemotherapy for patients with persistent vitreous or subretinal disease has become a very strong alternative to the use of systemic chemotherapy (refer to the Ophthalmic Artery Infusion of Chemotherapy [Intra-arterial Chemotherapy] and Intravitreal Chemotherapy sections of this summary for more information).
[14]
[15]
[17]
[18]
;
[16]
[Level of evidence: 3iiDiv] While tandem administration is feasible, bilateral administrations increase the risk of systemic toxicity caused by melphalan exposure.
[25]
In these circumstances, intra-arterial chemotherapy with single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure.
[26]
These treatments should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.

Treatment of Cavitary Retinoblastoma

Treatment options for cavitary retinoblastoma include the following:

Systemic and/or intra-arterial chemotherapy.

In patients with cavitary retinoblastoma, minimal visual response is seen after intravenous chemotherapy and/or intra-arterial chemotherapy. Despite the blunted clinical response, cavitary retinoblastoma has a favorable long-term outcome, with stable tumor regression and globe salvage. Aggressive or prolonged chemotherapy or adjunctive therapies are generally not necessary. In a retrospective series of 26 cavitary retinoblastomas that were treated with intravenous chemoreduction and/or intra-arterial chemotherapy, the mean reduction in tumor base was 22%, and the mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only one eye, globe salvage was achieved in 22 eyes, and there were no cases of metastasis or death during 49 months (range, 6–189 months) of follow-up.
[27]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Extraocular Retinoblastoma

In high-income countries, few patients with retinoblastoma present with extraocular
disease. Extraocular disease may be localized to the soft tissues surrounding
the eye or to the optic nerve beyond the margin of resection. However, further
extension may progress into the brain and meninges, with subsequent seeding of the
spinal fluid and as distant metastatic disease involving the lungs, bones,
and bone marrow.

Treatment of Orbital and Locoregional Retinoblastoma

Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera. For this reason, transscleral disease is considered to be extraocular and should be treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases.

Treatment options for extraocular retinoblastoma (orbital and locoregional) include the following:

Chemotherapy.

Enucleation (for extraocular extension).

Radiation therapy.

Treatment includes systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Because most recurrences occur in the central nervous system (CNS), regimens that include drugs with well-documented CNS penetration are used. Different chemotherapy regimens have proven to be effective, including vincristine, cyclophosphamide, and doxorubicin and platinum- and epipodophyllotoxin-based regimens, or a combination of both.
[1]
[2]
[3]

For patients with macroscopic orbital disease, delay of surgery until response to chemotherapy is achieved (usually after receiving two or three courses of treatment) has been effective. Patients then undergo enucleation and receive an additional four to six courses of chemotherapy. Next, local control is consolidated with orbital irradiation (40–45 Gy). Using this approach, orbital exenteration is not indicated.
[3]

Patients with isolated involvement of the optic nerve at the transsection level are considered to have extraocular disease and are treated using systemic therapy, similar to that used for macroscopic orbital disease, and irradiation of the entire orbit (36 Gy) with a 10 Gy boost to the chiasm (total of 46 Gy).
[2]

Treatment of CNS Disease

Intracranial dissemination occurs by direct extension through the optic nerve, and its prognosis is dismal. Treatment for these patients includes platinum-based, intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been used traditionally, there is no preclinical or clinical evidence to support its use.

Treatment options for extraocular retinoblastoma (CNS disease) include the following:

Systemic chemotherapy followed by myeloablative chemotherapy and stem cell rescue with or without radiation therapy.

The administration of radiation therapy to these patients is controversial. Responses have been observed with craniospinal radiation using 25 Gy to 35 Gy to the entire craniospinal axis and a boost (10 Gy) to sites of measurable disease.

Therapeutic intensification with high-dose, marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue has been explored, but its role is not yet clear.
[4]
[Level of evidence: 3iiA]

Treatment of Synchronous Trilateral Retinoblastoma

Trilateral retinoblastoma is usually associated with a pineal lesion or, less commonly, a suprasellar lesion.
[5]
[6]
[7]
In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than of a primary intracranial focus, such as a pineal tumor. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months.
[8]
[9]
However, with increased surveillance and aggressive therapy, there has been improvement in survival, from 6% (patients treated before 1995) to 44% (patients treated after 1996).
[10]

Treatment options for synchronous trilateral retinoblastoma include the following:

Systemic chemotherapy followed by surgery and myeloablative chemotherapy with stem cell rescue.

Systemic chemotherapy followed by surgery and radiation therapy.

While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding radiation by using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to those being used in the treatment of brain tumors in infants.
[11]

Treatment of Extracranial Metastatic Retinoblastoma

Treatment options for extracranial metastatic retinoblastoma include the following:

Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy.

Hematogenous metastases may develop in the bones, bone marrow and, less frequently, the liver. Although long-term survival has been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In the last two decades, however, studies of small series of patients have shown that metastatic retinoblastoma can be cured using high-dose, marrow-ablative chemotherapy and autologous hematopoietic stem cell rescue.
[12]
[13]
[14]
[15]
[16]
[17]
[18]
;
[19]
[Level of evidence: 3iiA]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Progressive or Recurrent Retinoblastoma

The prognosis for a patient with progressive or recurrent retinoblastoma
depends on the site and extent of the progression or recurrence and previous treatment received. Intraocular and extraocular recurrences have very different prognoses and are treated in distinctly different ways.

Treatment of Progressive or Recurrent Intraocular Retinoblastoma

Treatment options for progressive or recurrent intraocular retinoblastoma include the following:

New intraocular tumors can arise in patients with the heritable form of disease whose eyes have been treated with local control measures only, because every cell in the retina carries the RB1 mutation; this should not be considered a recurrence. Even with previous treatment consisting of chemoreduction and local control measures in very young patients with heritable retinoblastoma, surveillance may detect new tumors at an early stage, and additional local control therapy, including plaque radiation therapy, can be successful in eradicating the tumors.
[1]

When the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis for sight and survival may be excellent with local therapy only.
[2]
[Level of evidence: 3iiDiv] If the recurrence or progression is confined to the
eye but is extensive, the prognosis for sight is poor; however, survival
remains excellent.

Intra-arterial chemotherapy into the ophthalmic artery has been effective in patients who relapse after systemic chemotherapy and radiation therapy.
[3]
[4]
Rescue intra-arterial chemotherapy has been used after primary intra-arterial chemotherapy. However, patients often require other treatment methods because of disease progression after second-line intra-arterial chemotherapy.
[5]
Radiation therapy should be considered for patients who have not been previously irradiated. Finally, enucleation may be required in cases of progressive disease after all eye-salvaging treatments have failed.

Treatment of Progressive or Recurrent Extraocular Retinoblastoma

Treatment options for progressive or recurrent extraocular retinoblastoma include the following:

Systemic chemotherapy and radiation therapy for orbital disease.

Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy for extraorbital disease.

Recurrence in the orbit after enucleation is treated with aggressive chemotherapy in addition to local radiation therapy because of the high risk of metastatic disease.
[6]
[Level of evidence: 3iiA] After enucleation for recurrence, high-resolution magnetic resonance imaging with orbital coils can be helpful in distinguishing orbital recurrence from postsurgical enhancement.
[7]

If the recurrence or progression is extraocular, the
chance of survival is poor.
[8]
However, the use of intensive systemic chemotherapy and consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue may improve the chance of a cure, particularly for patients with extracranial recurrence (refer to the Treatment of Extraocular Retinoblastoma section of this summary for more information). For patients with disease recurrence after those intensive approaches, clinical trials
may be considered.

Treatment Options Under Clinical Evaluation for Progressive or Recurrent Retinoblastoma

One approach under investigation for patients with progressive intraocular retinoblastoma includes the use of an oncolytic adenovirus that targets RB1.
[9]

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

APEC1621 (NCT03155620)

:

NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Retinoblastoma Treatment are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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